Nitric oxide (NO) is a gas that in animals participates in a wide variety of functions in the cardiovascular, immune and nervous systems. It has an unpaired electron in its π orbital, and this characteristic gives NO special properties. Nitric oxide can react with different macromolecules (proteins, lipids, nucleic acids, etc.) and diffuse through cell membranes. The term reactive nitrogen species (RNS) has also been introduced in the biological literature to designate nitric oxide and other NO-related molecules, such as S-nitrosothiols (RSNOs), peroxynitrite (ONOO—), dinitrogen trioxide (N2O3) and nitrogen dioxide (NO2) among others, which have relevant roles in multiple physiological processes of animal and plant cells. These molecules directly or indirectly are involved in post-translational modifications in cell signaling under physiological and pathological conditions including binding to metal centers, S-nitrosylation of thiol groups and nitration of tyrosine (Corpas, et al., Plant Signal Behav., 4(10): 920-923 (2009)).
For example, tyrosine nitrated proteins constitute a widespread finding in the normal or diseased cardiovascular (CV) system (Peluffo and Radi, Cardiovasc. Res., 75(2):291-302 (2007)). In the various compartments and tissues of the CV system, namely, intravascular space, vessel wall and myocardium, nitrated proteins have been detected with a variety of techniques (reviewed in Bartesaghi, et al., Amino Acids, 32:501-515 (2007) and Ye, et al., Methods Enzymol., 269:201-209 (1996)), and have been implicated in various cardiovascular and pulmonary pathologies. In many cases the protein target that is nitrated is an enzyme or signaling protein whose function is altered by nitration.
Current methods of treating protein nitration and the myriad of pathologies associated therewith are insufficient.
Therefore, it is an object of the invention to provide compositions and methods for preventing, blocking or otherwise reducing protein nitration.
It is also an object of the invention to use compositions for blocking or reducing protein nitration to treat or prevent one or more symptoms of a disease associated with or caused by protein nitration.
It is a further object of the invention to reduce nitration-associated endothelial hyperpermeability in a subject.
It is also a further object of the invention to reduce or prevent nitration-associated increases in vascular smooth muscle cell proliferation in a subject.
It is a further object of the invention to treat one of more symptoms of vascular pulmonary hypertension and other vascular diseases and disorders in a subject.